title: Pharmacokinetics of novel atrial-selective antiarrhythmic agent vernakalant hydrochloride injection (RSD1235): influence of CYP2D6 expression and other factors.
abstract: Vernakalant hydrochloride injection (RSD1235) is a relatively atrial-selective antiarrhythmic agent that converts atrial fibrillation rapidly to sinus rhythm. The pharmacokinetics of vernakalant were explored in healthy volunteers and in patients with atrial fibrillation or atrial flutter in 4 clinical studies. Key pharmacokinetic parameters analyzed were the maximum plasma concentration and the area under the plasma concentration-time curve. Vernakalant exhibited linear pharmacokinetics over the dose range of 0.1 mg/kg to 5.0 mg/kg in healthy subjects, and generally showed dose proportionality in patients with atrial fibrillation or atrial flutter who received 1 or 2 vernakalant infusions. Vernakalant was metabolized rapidly via 4-O-demethylation by cytochrome P450 (CYP)2D6 to its major metabolite RSD1385, which then circulated predominantly as an inactive glucuronide conjugate. In most patients, the maximum plasma concentration of RSD1385 glucuronide exceeded that of vernakalant. Unconjugated RSD1385 was found at low levels in all patients demonstrating either a cytochrome P450 CYP2D6 "extensive metabolizer" or "poor metabolizer" phenotype or genotype; however, CYP2D6 poor metabolizers had even lower levels of unconjugated RSD1385. The impact of CYP2D6 metabolizer status on vernakalant exposure was explored in patients with atrial fibrillation or atrial flutter who received a therapeutic regimen (3 mg/kg initially via 10-minute intravenous infusion followed by a second 2 mg/kg 10-minute infusion if atrial fibrillation persisted after a 15-minute observation period). In the subset that received 2 vernakalant infusions, there was little difference in vernakalant maximum plasma concentration or area under the plasma concentration-time curve from the start of the first infusion to 90 minutes between CYP2D6 poor metabolizers and extensive metabolizers or between those who did or did not receive concomitant CYP2D6-inhibitor medications. Gender, age, and renal function did not have a clinically significant influence on the pharmacokinetics of vernakalant. These results suggest that an assessment of CYP2D6 expression may not be needed when vernakalant is administered acutely and intravenously to patients with atrial fibrillation.
authors.affiliation: Astellas Pharma US Inc, Three Parkway North, Deerfield, IL 60015, USA.
authors.forename: Zhongping L
authors.initials: ZL
authors.lastname: Mao
authors.forename: Jeffery J
authors.initials: JJ
authors.lastname: Wheeler
authors.forename: Lilian
authors.initials: L
authors.lastname: Clohs
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Beatch
authors.forename: James
authors.initials: J
authors.lastname: Keirns
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000840:Anisoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000503:physiopathology; D019389:Cytochrome P-450 CYP2D6 / Q000008:administration & dosage / Q000096:biosynthesis*; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006325:Heart Atria; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012737:Sex Factors; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D011759:Pyrrolidines; C524581:vernakalant; D019389:Cytochrome P-450 CYP2D6